tbuckley/cabot-search huggingface dataset:
Abstract 4041: Use of Receptor Occupancy Assays on cells from Peripheral Blood as a Surrogate Model of the Tumor Microenvironment
Authors: Nicholas Jones, Brian Ngo, Benjamin Fancke, Jessica Limson, Floyd Davis
Journal: Cancer Research (2022)

Abstract In the development of monoclonal antibodies for the treatment of solid tumors, monitoring receptor occupancy (RO) on peripheral blood lymphocytes can help illustrate potential therapeutic activity occurring in the tumor environment as an assessment of pharmacodynamics (PD). There is increased interest in using these PD assessments on cells from the periphery to assess the effectiveness and efficacy of investigational therapies. In this area of therapeutic development, much focus has been placed on checkpoint inhibitors proteins/receptors such as PD-1, PD-L1, TIM3, CTLA-4, TIGIT, and multiple others. These immune checkpoint inhibitors are suitable targets since they can be upregulated and/or modulated on exhausted T cells in cancer patients. Assessing the expression of these markers in the tumor itself would be an invasive process and provide little information to correlate with pharmacokinetic results throughout the course of a clinical trial to determine optimal dose selection. However, assessment of the receptor expression and occupancy in combination with pharmacokinetics can lead to a better understanding of drug levels required to achieve optimal therapeutic performance. Monitoring the expression and binding of these molecules by drug can determine specific treatment based on the ability of the patient’s own immune system to act, while providing information to identify therapeutic responses against cancer. This poster will present an example of one such RO assessment in its development and implementation. Citation Format: Nicholas Jones, Brian Ngo, Benjamin Fancke, Jessica Limson, Floyd Davis. Use of Receptor Occupancy Assays on cells from Peripheral Blood as a Surrogate Model of the Tumor Microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4041.
Abstract 4106: Curating protein complexes from multiple resources and validate their co-regulations at RNA/protein level in pan-cancer
Authors: Yizhe Song, Daniel Cui Zhou, Yize Li, Liang-Bo Wang, Michael C. Wendl, Gad Getz, Li Ding
Journal: Cancer Research (2022)

Abstract Protein complexes are sets of proteins that not only physically interact with each other, but also play important roles in progression of diseases like cancer. However, little is known about the co-regulation patterns of complexes and how many of them could be potential therapeutic targets. We collected 16,680 complexes from CORUM, Reactome, Complex Portal, and Havugimana PC. Harmonization of subunits of complexes by UniProt ID removed 4,112 redundant complexes. We further found that 3,018/12,559 complexes have at least one cancer driver gene involved, of which 2,408 complexes were found to have druggable genes, according to CiVic and OncoKB. Co-regulation patterns of 12,559 complexes were annotated utilizing gene expression and protein expression data from 1,101 cases across 10 cancer types (BR, COAD, OV, UCEC, HNSCC, PDAC, LSCC, LUAD, GBM, and ccRCC) from the Clinical Proteomic Tumor Analysis Consortium (CPTAC). Pairwise correlations across subunits of each complex at protein and RNA levels were calculated separately. Correlation &amp;gt;0.8 would suggest strong interaction of the subunits of the complex. Protein-only co-regulation complex was declared for protein pairwise correlation &amp;gt;0.8 and RNA pairwise correlation &amp;lt;0.5. RNA-only co-regulation complex was defined vice versa. We found more protein-only co-regulation complexes than RNA-only co-regulation complexes. This validated that RNA expression doesn’t always correlate with protein expression and few complexes were co-regulated at both RNA and protein levels. Our study suggests the value of utilizing proteome data to understand the formation of complex and inner relationships between subunits of complexes. Citation Format: Yizhe Song, Daniel Cui Zhou, Yize Li, Liang-Bo Wang, Michael C. Wendl, Gad Getz, Li Ding. Curating protein complexes from multiple resources and validate their co-regulations at RNA/protein level in pan-cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4106.
Abstract 5642: Discovery of SCR-8079, a novel and selective CDK2/4/6 inhibitor overcomes the resistance to CDK4/6 inhibition and demonstrates broad anti-tumor activities in breast cancers
Authors: Feng Zhou, Guimei Yang, Feng Tang, Yan Zhang, Wenqing Yang, Liting Xue, Ping Chen, Renhong Tang
Journal: Cancer Research (2022)

Abstract The CDK4/6 inhibitor, palbociclib (PAL), significantly improves progression-free survival and overall survival in HR positive and HER2-negative breast cancer in combination either with letrozole or fulvestrant. However, resistance to the CDK4/6 inhibition inevitably develops. Preclinical models and clinical transcriptome specimen analysis disclosed that abnormal activation of Cyclin E/CDK2 due to CCNE gene amplification was one of the major reasons to CDK4/6 inhibition resistance. And inhibition of CDK2 either by gene knockdown of CCNE or by pharmaceutic approach rescued the sensitivity of resistant tumor cells to CDK4/6 inhibition. To overcome the resistance, a novel and selective CDK2/4/6 inhibitor, SCR-8079 was developed. In biochemical assay, SCR-8079 was demonstrated high potency on inhibiting CDK2/4/6 with IC50 of 3 nM, 1 nM and 2 nM, respectively. And SCR-8079 showed good selectivity over CDK1/9 isoforms (&amp;gt;60 selectivity folds). SCR-8079 demonstrated closed inhibitory activities both on CDK4/6 sensitive and resistant lines. In MCF-7, a breast cancer cell line sensitive to PAL, SCR-8079 potently inhibited Rb phosphorylation (IC50, 53 nM) and cell proliferation (IC50, 28 nM). Meanwhile, SCR-8079 showed high potency on inhibiting on the growth of OVCAR3, an ovarian cancer cell line with elevated CDK2 activation and resistance to PAL. SCR-8079 inhibited Rb phosphorylation (IC50, 41 nM) and cell proliferation (IC50, 21 nM). In order to further mimic CDK4/6 resistance, a PAL resistant line (MCF-7R) was generated via induction of MCF-7 by gradient increased PAL. SCR-8079 potently inhibited MCF-7R cells growth (IC50, 3 nM) but PAL didn’t (IC50 &amp;gt;1 µM). Moreover, SCR-8079 showed high potency on growth inhibition in a broad of breast cancer cell lines, including HR-positive, Her2-positive and triple negative lines. SCR-8079 displayed good oral bioavailability in multiple pre-clinical species and robust anti-tumor activities both in OVCAR3 and MCF7 xenograft models. In summary, SCR-8079 is a selective CDK2/4/6 inhibitor, which overcomes the CCNE-mediated resistance to CDK4/6 inhibition. Broad anti-tumor activity suggests SCR-8079 central role in breast cancer treatment. Citation Format: Feng Zhou, Guimei Yang, Feng Tang, Yan Zhang, Wenqing Yang, Liting Xue, Ping Chen, Renhong Tang. Discovery of SCR-8079, a novel and selective CDK2/4/6 inhibitor overcomes the resistance to CDK4/6 inhibition and demonstrates broad anti-tumor activities in breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5642.
Abstract 6053: Characterizing plasticity of chemotherapy-tolerant persister cells in rhabdomyosarcoma
Authors: Weiliang Tang, Madeline Fritzke, Spencer Stinson, Eleanor Chen
Journal: Cancer Research (2022)

Abstract Rhabdomyosarcoma (RMS) is a rare pediatric soft tissue sarcoma (250-300 cases a year in the US). The prognosis for patients with relapsed and metastatic disease remains poor with less than 30% overall survival rate. Current treatment regimens are ineffective against relapsed disease of RMS. There remains the urgent to need to identify more effective therapy options. While some studies have demonstrated up-regulation of multi-drug resistance genes and abnormal activity of selected signaling pathways in chemotherapy-resistant RMS tumors, the cellular and molecular mechanisms underlying adaptive cell changes leading to persistent survival of treatment-resistant RMS cells remain poorly understood. The stem cell-like tumor propagating cells (TPCs) have the capacity for self-renewal and are thought to be responsible for initiating treatment-resistant relapse and metastasis of some cancer types. The drug-tolerant persister (DTP) cell population with stem-cell like features has been shown in some cancer types to exhibit plasticity in cell state and dynamic changes in chromatin and transcriptional activity. A better understanding of how the cellular plasticity of the DTPs is regulated is critical for developing therapies to overcome treatment resistance in RMS. We have shown that initial treatment of RMS cells with standard-of-care cytotoxic agent, vincristine, selects for a DTP that is enriched with CD133+ stem-like cells. By gene expression studies, MYC and YBX1 driven-gene networks are upregulated in CD133+ cells. Targeted disruption of MYC and YBX1 by CRISPR/Cas9 reduces self-renewal capacity of RMS cells, and overexpression of MYC and YBX1 confers tolerance on RMS cells to vincristine. RMS cells treated in long-term culture with incremental increase in vincristine dose gives rise to late DTP with a distinct transcriptional profile including up-regulation of many genes regulated by the myogenic regulatory factor, MYOD1. MYC binds to the promoters of YBX1 and MYOD1. The findings suggest dynamic transcriptional changes and cell state plasticity of the DTPs in RMS. Our ongoing work includes characterizing the mechanisms by which MYC and MYOD1 regulate cell state plasticity and transcriptional adaptation of the DTP, assess inter- and intra-tumoral transcriptional heterogeneity of treatment-refractory RMS tumors and determine prognostic significance of functional network modules of MYC, MYOD and their downstream genes. Our ultimate goal is to translate our findings into more effective therapies for treatment-refractory RMS patients. Citation Format: Weiliang Tang, Madeline Fritzke, Spencer Stinson, Eleanor Chen. Characterizing plasticity of chemotherapy-tolerant persister cells in rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6053.
Abstract 773: Inhibition of ubiquitin receptor ADRM1 for the treatment of metastatic breast cancer
Authors: Christopher Andrews, Clayton Yates, Balasubramanyam Karanam
Journal: Cancer Research (2022)

Abstract Adhesion-regulating molecule 1 (ADRM1) is a polyubiquitin receptor on the 26S proteasome. ADRM1 is upregulated in many cancers. In this study, we evaluated the potential prognostic and predictive value of ADRM1 in breast cancer patients. We determined the expression of ADRM1 and its relationship to breast cancer subtypes, using the Cancer Genome Atlas dataset that contained racial and clinical outcomes data totaling 1108 patients. The ADRM1 mRNA expression levels were divided into quartiles to designate the ADRM1 high versus low expression designation. Karanam et. al developed an orally available proteasome inhibitor bis-benzylidine piperidone (RA190), that binds to the ubiquitin receptor RPN13/ADRM1 on the 19S regulatory particle of the proteasome and directly kills cancer cells by triggering proteotoxic stress. RA190 binds to cysteine 88 of ADRM1/RPN13, triggering rapid accumulation of high-molecular-weight poly-ubiquitinated proteins resulting in apoptosis. Up284 is one of a second generation of small molecules that mimic RA190 activity. The objective of this study is to verify the role of ubiquitin receptor RPN13/ADRM1 in metastatic breast cancer samples of European American and African American patients and identify the safe combination of regimens of bortezomib in combination with Up289 to mitigate recurrence, metastasis and reduce mortality in AA TNBC/QNBC. Clinically, this will reveal a new, hitherto unknown targeted regimen for AA QNBC. From the biological perspective, it will provide insights into the underlying molecular changes that are associated with health disparities. Currently available treatments are unable to eradicate metastatic breast cancer specifically those classified as QNBC. Our preliminary analysis of Cancer Genome Atlas (TCGA) indicated that ADRM1 expression is highly expressed in AA versus EA breast cancer patients, resulting in a worse overall survival. Further analysis of ADRM1 in QNBC patients indicated that it was significantly elevated predominantly in African American patients with QNBC. Citation Format: Christopher Andrews, Clayton Yates, Balasubramanyam Karanam. Inhibition of ubiquitin receptor ADRM1 for the treatment of metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 773.
Abstract 5826: Autophagy regulates cancer stem cell properties in triple negative breast cancer via miR-181a-mediated regulation of ATG5/ATG2B
Authors: Jong Hoon Park, Jee Won Park, Yesol Kim, Jaehee Jun, Yejin Ahn
Journal: Cancer Research (2022)

Abstract Autophagy has a dual role in the maintenance of cancer stem cells (CSCs), but the precise relationship between autophagy and cancer stemness requires further investigation. In this study, it was found that luminal and triple-negative breast cancer require distinct therapeutic approaches because of their different expressions of autophagy flux. We identified that autophagy flux was inhibited in triple-negative breast cancer (TNBC) CSCs. Moreover, miRNA-181a (miR-181a) is upregulated both in TNBC CSCs and patients. ATG5 and ATG2B participate in the early formation of autophagosomes and were revealed as targets of miR-181a. Inhibition of miR-181a expression led to attenuation of TNBC cancer stemness and an increase in autophagy flux. Furthermore, treatment with curcumin led to attenuation of cancer stemness in TNBC CSCs; the expression of ATG5 and ATG2B was enhanced and there was an increase of autophagy flux. These results indicated that ATG5 and ATG2B are involved in the suppression of cancer stemness in TNBC. In summary, autophagy inhibits cancer stemness through the miR-181a-regulated mechanism in TNBC. Promoting tumor-suppressive autophagy using curcumin may be a potential method for the treatment of TNBC. Citation Format: Jong Hoon Park, Jee Won Park, Yesol Kim, Jaehee Jun, Yejin Ahn. Autophagy regulates cancer stem cell properties in triple negative breast cancer via miR-181a-mediated regulation of ATG5/ATG2B [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5826.
Abstract 5898: Bone morphogenic protein receptor 2 (<i>BMPR2</i>) as a potential germline driver in Juvenile Polyposis Syndrome (JPS)
Authors: Suzanne P. MacFarland, Bridgid Greed, Michael H. Xie, Garrett M. Brodeur, Zvi Cramer, Maiah H. Dent, Melani M. Duvall, Kathryn E. Hamilton, James Howe, Tatiana Karakasheva, Petar Mamula, Christopher Lengner
Journal: Cancer Research (2022)

Abstract Summary: Juvenile Polyposis Syndrome is a pediatric cancer predisposition syndrome for which approximately half of patients do not have a known germline driver; we propose BMPR2 as a possible germline driver of disease in mutation-negative JPS. Background: Juvenile Polyposis Syndrome (JPS) is a cancer predisposition syndrome characterized in some cases by inactivating germline mutations in BMPR1A or SMAD4. However, in 40-60% of patients the germline driver is unknown. Methods: Through whole exome sequencing, an individual with high polyp burden and negative genetic testing for variants in SMAD4 and BMPR1A was found to have a potentially inactivating germline variant in BMPR2. Under an IRB-approved protocol, patient-derived, three-dimensional organoids were established from adjacent colon and polyp tissue of this individual, as well as an individual with a BMPR1A deletion and age- and sex-matched controls. Proliferation, metabolic activity, and protein expression of each line were measured by Western blot, Ki67 staining, EdU labelling, cell titer glo (CTG) assay. Results: Distinct phenotypic differences are evident between colonoids from an individual with a BMPR1A deletion and both the colon and polyp BMPR2 variant colonoids, such as increased crypt budding and Ki67 staining. CTG assay data indicate higher metabolic activity in BMPR2 variant colonoids in comparison to normal controls (p= 0.0104.) Through Western blot analysis, both BMPR2 colon and polyp colonoids showed decreased SMAD4 expression and phosphorylation. Conclusions: These data demonstrate that clear phenotypic differences exist between colonoid lines established from normal controls, individuals with known JPS predisposition genes, and a novel candidate driver of disease, BMPR2. Proliferation and protein expression data suggest that both known and candidate genotypes are consistent with a hyperproliferative phenotype. In vitro data support BMPR2 as a candidate germline driver of the JPS phenotype, and additional study is ongoing regarding downstream pathway regulation in colonoids with a BMPR2 variant. Citation Format: Suzanne P. MacFarland, Bridgid Greed, Michael H. Xie, Garrett M. Brodeur, Zvi Cramer, Maiah H. Dent, Melani M. Duvall, Kathryn E. Hamilton, James Howe, Tatiana Karakasheva, Petar Mamula, Christopher Lengner. Bone morphogenic protein receptor 2 (BMPR2) as a potential germline driver in Juvenile Polyposis Syndrome (JPS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5898.
Abstract 1713: Delineation of cell subpopulations and cell cell interactions to determine correlations between drug response and tumor microenvironment in early-stage lung cancer
Authors: Corinne Ramos, Journe Anne Sophie, Amandine Gerstenberg, Fabien Pamelard, Jonathan Stauber
Journal: Cancer Research (2022)

Abstract Purpose The tumor microenvironment (TME) is an integral player in cancer initiation, tumor progression, response and resistance to anti-cancer therapy. Understanding the complex interactions of tumor immune architecture has therefore become increasingly desirable to guide patient selection. Conventional studies that underestimate the potential value of the spatial architecture of the TME are unable to completely elucidate its complexity. To overcome these limitations, we used quantitative image analysis based on multiplexed immunohistochemistry and deep learning technologies to interrogate complex information from the tumor microenvironment and find predictive insights into treatment response for non-small cell lung cancer (NSCLC). Method We used tumor tissues samples from resected NSCLC (adenocarcinoma and squamous cell carcinoma) tumors treated with adjuvant pembrolizumab therapy. Patient frozen tissue sections were prepared and stained using a panel of 20 immune or tumor-related antibodies. Different metal tags were assigned to each antibody. The stained cells were then detected and analyzed by the Hyperion™ Imaging System. Further data analysis was performed using proprietary workflow to identify which cells are influencing the treatment response and how they are spatially distributed relative to each other. Results Tumor samples of NSCLC with similar clinical characteristics at the T1N0M0 had different cells types, including CD4+ T cells, CD8+ T cells, CD20+ B cells, CD14+ macrophages, CD56+ natural killer cells, granulocytes, etc. More immunosuppressive cells were found in the sample of patient that did not respond to immunotherapy illustrating that differences in the tumor microenvironment of samples may contribute to different patients’ resistance to immunotherapy. Moreover, unsupervised clustering analysis reveal cell type signatures that are relevant to the prognoses of NSCLC. Conclusion High-multiplexed proteomics analyses using the Hyperion imaging system help identify and analyze the tumor microenvironment heterogeneity of NSCLC and explain the factors leading to different prognoses for NSCLC patients despite the same TNM stage. Furthermore, additional information for screening drugs for targeted therapy was found, that could greatly improve NSCLC treatments’ individualization. Citation Format: Corinne Ramos, Journe Anne Sophie, Amandine Gerstenberg, Fabien Pamelard, Jonathan Stauber. Delineation of cell subpopulations and cell cell interactions to determine correlations between drug response and tumor microenvironment in early-stage lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1713.
Abstract 6263: A pilot study to survey the exposure to secondhand smoke at home and at the workplace in Pakistan
Authors: Shagufta Rehmat, Faisal F. Khan
Journal: Cancer Research (2022)

Abstract Globally over 7 million deaths are attributed to direct tobacco consumption whereas about 1.2 million people die due to the exposure to secondhand smoke (SHS). The health complications and mortalities caused by SHS exposure in Pakistan are also very prominent as it causes more than 33 thousand annual deaths. In this pilot study, we wanted to evaluate the exposure to secondhand smoke at work and at home, and its association with the prevalence of diseases through a survey based cross-sectional study. An online questionnaire was designed and developed using Google Forms and a short link was distributed using social media channels (i.e., WhatsApp groups and Facebook). Respondents were young adults from all cities of Pakistan who had access to internet and were digitally literate. Exposure to secondhand smoke at home, during childhood (from 0-18 year of age), adulthood exposure (after 18 years of age), and exposure at work was evaluated. The data was analyzed using Microsoft Excel and R.A total of 438 respondents participated in this survey with representation of male (54%) and female (46%) belonging to major cities in Pakistan, including Peshawar (38%), Islamabad (10.4%), Lahore (7.2%), and Karachi (6%). Overall, 75% of the study cohort were exposed to SHS, with the highest exposure noticed during adulthood with 70.3% of people being exposed to SHS after 18 years of age. Amongst those who were exposed daily at home, 63% had chronic bronchitis while 60% had cardiac diseases as self-reported health issues. Those exposed to SHS during childhood for 2 or more than 2 hours per week, 80% had self-reported chronic bronchitis in the survey. During adulthood, universities dominated as a location that offered highest exposure to SHS for 2 or more than 2 hours/week. One-year exposure history at workplace revealed that of those who were exposed to SHS at work ‘several times a day’, 60% had high blood pressure, 55% had asthma, while 50% had chronic bronchitis. At home ‘the father’ was identified as the main source of secondhand smoke and during adulthood universities are identified as place of highest exposure. At workplaces although the percentage of people exposed to secondhand smoke is lesser than those reported in previous studies but the correlation with medical complications was revealing. Overall throat irritation, gastric issues, and eye irritations were highly reported medical conditions amongst exposed individuals. Citation Format: Shagufta Rehmat, Faisal F. Khan. A pilot study to survey the exposure to secondhand smoke at home and at the workplace in Pakistan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6263.